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Astrophysical collisionless shocks are among the most powerful particle accelerators in the Universe. Generated by violent interactions of supersonic plasma flows with the interstellar medium, supernova remnant shocks are observed to amplify magnetic fields 1 and accelerate electrons and protons to highly relativistic speeds 2 – 4 . In the well-established model of diffusive shock acceleration 5 , relativistic particles are accelerated by repeated shock crossings. However, this requires a separate mechanism that pre-accelerates particles to enable shock crossing. This is known as the ‘injection problem’, which is particularly relevant for electrons, and remains one of the most important puzzles in shock acceleration 6 . In most astrophysical shocks, the details of the shock structure cannot be directly resolved, making it challenging to identify the injection mechanism. Here we report results from laser-driven plasma flow experiments, and related simulations, that probe the formation of turbulent collisionless shocks in conditions relevant to young supernova remnants. We show that electrons can be effectively accelerated in a first-order Fermi process by small-scale turbulence produced within the shock transition to relativistic non-thermal energies, helping overcome the injection problem. Our observations provide new insight into electron injection at shocks and open the way for controlled laboratory studies of the physics underlying cosmic accelerators. In laser–plasma experiments complemented by simulations, electron acceleration is observed in turbulent collisionless shocks. This work clarifies the pre-acceleration to relativistic energies required for the onset of diffusive shock acceleration.

The test-negative design (TND) has become a standard approach for vaccine effectiveness (VE) studies. However, previous studies suggested that it may be more vulnerable than other designs to misclassification of disease outcome caused by imperfect diagnostic tests. This could be a particular limitation in VE studies where simple tests (e.g. rapid influenza diagnostic tests) are used for logistical convenience. To address this issue, we derived a mathematical representation of the TND with imperfect tests, then developed a bias correction framework for possible misclassification. TND studies usually include multiple covariates other than vaccine history to adjust for potential confounders; our methods can also address multivariate analyses and be easily coupled with existing estimation tools. We validated the performance of these methods using simulations of common scenarios for vaccine efficacy and were able to obtain unbiased estimates in a variety of parameter settings.

Background The acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine, and rivastigmine are commonly used in the management of various forms of dementia. Objectives While these drugs are known to induce classic cholinergic adverse events such as diarrhea, their potential to cause psychiatric adverse events has yet to be thoroughly examined. Methods We sought to determine the risk of psychiatric adverse events associated with the use of AChEIs through a systematic review and meta-analysis of double-blind randomized controlled trials involving patients with Alzheimer’s dementia and Parkinson’s dementia. Results A total of 48 trials encompassing 22,845 patients were included in our analysis. Anorexia was the most commonly reported psychiatric adverse event, followed by agitation, insomnia, and depression. Individuals exposed to AChEIs had a greater risk of experiencing appetite disorders, insomnia, or depression compared with those who received placebo (anorexia: odds ratio [OR] 2.93, 95% confidence interval [CI] 2.29–3.75; p < 0.00001; decreased appetite: OR 1.93, 95% CI 1.33–2.82; p  = 0.0006; insomnia: OR 1.55, 95% CI 1.25–1.93; p < 0.0001; and depression: OR 1.59, 95% CI 1.23–2.06, p  = 0.0004). Appetite disorders were also more frequent with high-dose versus low-dose therapy. A subgroup analysis revealed that the risk of insomnia was higher for donepezil than for galantamine. Conclusions Our findings suggest that AChEI therapy may negatively impact psychological health, and careful monitoring of new psychiatric symptoms is warranted. Lowering the dose may resolve some psychiatric adverse events, as may switching to galantamine in the case of insomnia. Clinical Trial Registration The study was pre-registered on PROSPERO (CRD42021258376).

The Cherenkov Telescope Array and the KM3NeT neutrino telescopes are major upcoming facilities in the fields of [Formula omitted]-ray and neutrino astronomy, respectively. Possible simultaneous production of [Formula omitted] rays and neutrinos in astrophysical accelerators of cosmic-ray nuclei motivates a combination of their data. We assess the potential of a combined analysis of CTA and KM3NeT data to determine the contribution of hadronic emission processes in known Galactic [Formula omitted]-ray emitters, comparing this result to the cases of two separate analyses. In doing so, we demonstrate the capability of Gammapy, an open-source software package for the analysis of [Formula omitted]-ray data, to also process data from neutrino telescopes. For a selection of prototypical [Formula omitted]-ray sources within our Galaxy, we obtain models for primary proton and electron spectra in the hadronic and leptonic emission scenario, respectively, by fitting published [Formula omitted]-ray spectra. Using these models and instrument response functions for both detectors, we employ the Gammapy package to generate pseudo data sets, where we assume 200 h of CTA observations and 10 years of KM3NeT detector operation. We then apply a three-dimensional binned likelihood analysis to these data sets, separately for each instrument and jointly for both. We find that the largest benefit of the combined analysis lies in the possibility of a consistent modelling of the [Formula omitted]-ray and neutrino emission. Assuming a purely leptonic scenario as input, we obtain, for the most favourable source, an average expected 68% credible interval that constrains the contribution of hadronic processes to the observed [Formula omitted]-ray emission to below 15%.

Questionnaire studies suggest that stroke patients experience sustained problems with sleep and daytime sleepiness, but physiological sleep studies focussing specifically on the chronic phase of stroke are lacking. Here we report for the first time physiological data of sleep and daytime sleepiness obtained through the two gold-standard methods, nocturnal polysomnography and the Multiple Sleep Latency Test. Data from community-dwelling patients with chronic right-hemispheric stroke (>12 months) were compared to sex- and age-matched controls. Behavioural and physiological measures suggested that stroke patients had poorer sleep with longer sleep latencies and lower sleep efficiency. Patients further spent more time awake during the night, and showed greater high-frequency power during nonREM sleep than controls. At the same time the Multiple Sleep Latency Test revealed greater wake efficiency in patients than controls. Importantly these findings were not due to group differences in sleep disordered breathing or periodic limb movements. Post-stroke insomnia is presently not adequately addressed within the care pathway for stroke. A holistic approach to rehabilitation and care provision, that includes targeted sleep interventions, is likely to enhance long-term outcome and quality of live in those living with chronic deficits after stroke.

Variation in methotrexate (MTX) efficacy represents a significant barrier to early and effective disease control in the treatment of autoimmune arthritis. We hypothesize that the utilization of metabolomic techniques will allow for an improved understanding of the biochemical basis for the pharmacological activity of MTX, and can promote the identification and evaluation of novel molecular biomarkers of MTX response. In this work, erythroblastoid cells were exposed to MTX at the physiologic concentration of 1,000 nM and analyzed using three metabolomic platforms to give a broad spectrum of cellular metabolites. MTX pharmacological activity, defined as cellular growth inhibition, was associated with an altered cellular metabolomic profile based on the analysis of 724 identified metabolites. By discriminant analysis, MTX treatment was associated with increases in ketoisovaleric acid, fructose, galactose, and 2‐deoxycytidine, and corresponding reductions in 2‐deoxyuridine, phosphatidylinositol 32:0, orotic acid, and inosine monophosphate. Inclusion of data from analysis of folate metabolism in combination with chemometric and metabolic network analysis demonstrated that MTX treatment is associated with dysregulated folate metabolism and nucleotide biosynthesis, which is in line with its known mechanism of action. However, MTX treatment was also associated with alterations in a diversity of metabolites, including intermediates of amino acid, carbohydrate, and lipid metabolism. Collectively, these findings support a robust metabolic response following exposure to physiologic concentrations of MTX. They also identify various metabolic intermediates that are associated with the pharmacological activity of MTX, and are, therefore, potential molecular biomarker candidates in future preclinical and clinical studies of MTX efficacy in autoimmune arthritis.

The commonly deleted region (CDR) for the 5q- syndrome has been identified as a 1.5-megabase interval on human chromosome 5q32. We studied, by real-time reverse-transcription (RT)-PCR, the expression of 33 genes within the CDR that are known to be expressed in CD34+ hematopoietic stem cells. Genes in the 5q- samples that showed the most pronounced decrease in expression compared to non-5q- samples were: solute carrier family 36, member 1 (SLC36A1; 89% downregulated), Ras-GTPase-activating protein SH3 domain-binding (G3BP; 79%), antioxidant protein 1 (ATOX1; 76%), colony-stimulating factor-1 receptor precursor (CSF1R; 76%), ribosomal protein S14 (RPS14; 74%), platelet-derived growth factor receptor-beta (PDGFRB; 73%), Nef-associated factor 1 (TNIP1; 72%), secreted protein, acidic and rich in cysteine (SPARC; 71%), annexin VI (ANAX6; 69%), NSDT (66%) and TIGD (60%). We further studied the hematopoietic system in SPARC-null mice. These mice showed significantly lower platelet counts compared to wild-type animals (P=0.008). Although hemoglobin, hematocrit and mean corpuscular volume (MCV) were lower in mice lacking SPARC, differences were not statistically significant. SPARC-null mice showed a significantly impaired ability to form erythroid burst-forming units (BFU-E). However, no significant differences were found in the formation of erythroid colony-forming units (CFU-E), granulocyte/monocyte colony-forming units (CFU-GM) or megakaryocyte colony-forming units (CFU-Mk) in these animals. We conclude that many of the genes within the CDR associated with the 5q- syndrome exhibit significantly decreased expression and that SPARC, as a potential tumor suppressor gene, may play a role in the pathogenesis of this disease.

Background Inadequate systemic exposure to infliximab (IFX) is associated with treatment failure. This work evaluated factors associated with reduced IFX exposure in children with autoimmune disorders requiring IFX therapy. Methods In this single-center cross-sectional prospective study IFX trough concentrations and anti-drug antibodies (ADAs) were measured in serum from children diagnosed with inflammatory bowel disease (IBD) ( n  = 73), juvenile idiopathic arthritis (JIA) ( n  = 16), or uveitis ( n  = 8) receiving maintenance IFX infusions at an outpatient infusion clinic in a tertiary academic pediatric hospital. IFX concentrations in combination with population pharmacokinetic modeling were used to estimate IFX clearance. Patient demographic and clinical data were collected by chart review and evaluated for their relationship with IFX clearance. Results IFX trough concentrations ranged from 0 to > 40 μg/mL and were 3-fold lower in children with IBD compared to children with JIA ( p  = 0.0002) or uveitis ( p  = 0.001). Children with IBD were found to receive lower IFX doses with longer dosing intervals, resulting in dose intensities (mg/kg/day) that were 2-fold lower compared to children with JIA ( p  = 0.0002) or uveitis ( p  = 0.02). Use of population pharmacokinetic analysis to normalize for variation in dosing practices demonstrated that increased IFX clearance was associated with ADA positivity ( p  = 0.004), male gender ( p  = 0.02), elevated erythrocyte sedimentation rate (ESR) (p = 0.02), elevated c-reactive protein (CRP) ( p  = 0.001), reduced serum albumin concentrations ( p  = 0.0005), and increased disease activity in JIA ( p  = 0.009) and IBD ( p  ≤ 0.08). No significant relationship between diagnosis and underlying differences in IFX clearance was observed. Multivariable analysis by covariate population pharmacokinetic modeling confirmed increased IFX clearance to be associated with anti-IFX antibody positivity, increased ESR, and reduced serum albumin concentrations. Conclusions Enhanced IFX clearance is associated with immunogenicity and inflammatory burden across autoimmune disorders. Higher systemic IFX exposures observed in children with rheumatologic disorders are driven primarily by provider drug dose and interval selection, rather than differences in IFX pharmacokinetics across diagnoses. Despite maintenance IFX dosing at or above the standard recommended range for IBD (i.e., 5 mg/kg every 8 weeks), the dosing intensity used in the treatment of IBD is notably lower than dosing intensities used to treat JIA and uveitis, and may place some children with IBD at risk for suboptimal maintenance IFX exposures necessary for treatment response.

The classification of tree species by remote sensing is an important task with a broad range of applications, including forest management, environmental monitoring, and climate change studies. Hyperspectral imaging has proven to be a valuable tool for this classification. Additionally, deep learning techniques have obtained outstanding results in hyperspectral classification. In this study, we apply a neural network to the classification of aerial hyperspectral images of trees. The study was conducted at a research station in southern Chile with 32 tree species. Our database has 3080 tree canopies that have been manually segmented and classified. The goal of the work was to study the correlation between forest structure complexity and classification performance across three different forest conditions: native forest, plantation of native species, and plantation of exotic species. The results show that classification performance is higher when forest structure and composition are simpler. We used a ResNet neural network as classifier and compared its performance with support vector machine and random forest. The best performance was obtained using ResNet in exotic plantations, the forest condition with the simplest structure, achieving an F1-score of 85.23%.

A growing number of infectious pathogens are spreading among geographic regions. Some pathogens that were previously not considered to pose a general threat to human health have emerged at regional and global scales, such as Zika and Ebola Virus Disease. Other pathogens, such as yellow fever virus, were previously thought to be under control but have recently re-emerged, causing new challenges to public health organisations. A wide array of new modelling techniques, aided by increased computing capabilities, novel diagnostic tools, and the increased speed and availability of genomic sequencing allow researchers to identify new pathogens more rapidly, assess the likelihood of geographic spread, and quantify the speed of human-to-human transmission. Despite some initial successes in predicting the spread of acute viral infections, the practicalities and sustainability of such approaches will need to be evaluated in the context of public health responses.